Detailed Characterization of T Cell Responses to HSV-2 in Immune Seronegative Persons

In 2003 we described a small cohort of subjects (n=6) who possessed no detectable serum antibodies to HSV-1 or HSV-2, no clinical or virological evidence of mucosal HSV infection yet possessed consistently detectable HSV-specific T cell responses measured primarily by lymphoproliferative (LP) and CTL assays to whole HSV-2 antigen. We termed these persons immune seronegative (IS). This report characterizes the T cell responses in 22 IS subjects largely recruited from studies of HSV-seronegative subjects in ongoing sexual relationships with HSV-2-seropositive (HSV-2+) partners using pools of overlapping peptides spanning 16 immuno-prevalent HSV-2 proteins. Overall, 77% of IS subjects had HSV-specific LP responses, 85% had IFN-γ ELISPOT responses to at least 1 HSV-2 peptide pool, and 55% had both LP and IFN-γ ELISPOT responses. In some cases, IFN-γ ELISPOT responses were in excess of 500 spot-forming cells per 10 6 PBMC and persisted for over 5 years. While HSV-2+ subjects (n=40) had frequent responses to glycoproteins, tegument and immediate-early (IE) proteins of HSV-2, T cell responses in IS subjects were directed primarily at UL39 and the IE proteins ICP4 and ICP0. These data suggest that the antigenic repertoire of T cells in IS subjects is skewed compared to HSV-2+ subjects and that IS subjects had more frequent T cells responses to IE proteins and infrequent T cell responses to virion components. Understanding the mechanism(s) by which such responses are elicited may provide important insights in developing novel strategies for preventing acquisition of sexually acquired HSV-2.